Generally, representative ophthalmology diseases in reference to angiogenesis are Diabetic retinopathy and Retinopathy of prematurity which blood vessels are formed in the cornea, and Age-related macular degeneration which blood vessels are formed in the choroid (Amal A. E. et al., Retina 11:244-249(1991); Constantin J. P. et al., Ophthalmology 97:1329-1333(1990); Jin-Hong C. et al., Current opinion in Ophthalmology 12:242-249(2001);Peter A. C., J of Cellular Physiology 184:301-310(2000)) and Glaucoma.
Retinopathy of prematurity (ROP) is a major cause of loss of eyesight in infants and occurs through two-step. Premature infants have an incomplete retinal blood vessel at the beginning of a birth, especially the premature infants who suffer from the progress of ROP have a risk of inducing no growth of blood vessel in a retina (Flynn J. T. et al., Arch Ophthalmol 95:217-223 (1977)). As a result, the retina is formed in a blood vessel-free state, resulting in formation of a low-oxygen peripheral retina (step 1 of ROP). In such step 1 of ROP, a non-perfusion level of retina determines a destructive stage including a retinal detachment and blindness caused by angiogenesis (step 2 of ROP) (Penn J. S. et al., Invest Ophthalmol Vis Sci 35:3429-435 (1994)). If blood vessel is normally developed in the retina of the premature infants, then a destructive stage may not be initiated due to a secondary angiogenesis in ROP. It has been known that use of high concentration of oxygen is associated with such diseases, which means that an oxygen-regulated factor is present in the retina of premature infants.
It is anticipated that vascular endothelial growth factor (VEGF), which is necessarily required to a normal angiogenesis and known as a oxygen-regulated factor, should take a important role in ROP, but it is known from the various studies that VEGF act mainly in the first and secondary stage of ROP (Pierce E.A. et al., Arch Ophthalmol 114:1219-1228 (1996)). It was studied that VEGF expression is inhibited in the first stage to affect the growth of blood vessel, using ROP animal model (for example, high supplement oxygen).
Diabetic retinopathy is one of the most well known conditions among microvessel-related complication mainly caused by hyperglycemia, and become a primary cause of acquired loss of sight in the adult (Brownlee M., Nature 414:813-820 (2001)). A serious loss of sight associated with diabetic retinopathy is generated by means to retinal angiogenesis (Battegay E. J., J Mol Med 73:333-346 (1995)) and therefore vitreous hemorrhage and 4 tractional retinal detachment (Cai J., Boulton M., Eye 16:242-260(2002)). Referring to a pathophysiological change in the retina of diabetic patients, the conditions such as loss of cells surrounding capillary vessel, growth of basement membrane, loss of automatic control function in retinal blood vessel, abnormality of capillary circulation, microaneurysm, IRMA (intraretinal microvascular abnormalities) have appeared, finally resulting in formation of an area of retinal non-perfusion (Lip P. L. et al., Invest Ophthalmol Vis Sci 41:2115-2119 (2000); Hammes H. P. et al., Diabetes 51:3107-3112 (2002)). Such changes induce an increased vascular permeability, chronic retinal hypoxia and retinal ischemia through their continuous development to form macular edema or angiogenesis, resulting in progress into proliferative diabetic retinopathy (Aiello L. P. et al., Diabetes Care 21:143-156 (1998)). It seems that diabetic patients have an increased level of a factor VEGF, and then the increased factor induces a retinopathy by destroying a retinal blood barrier.
Age-related macular degeneration is one of the major causes of blindness which appears over 50 years old. Severe loss of sight results from angiogenesis induced from capillary vessel of a choroidal neovascular membrane (Ferris F. L. 3rd et al., Arch Ophthalmol 102:1640-1642 (1984)). AMD is generally divided in 2 different types, for example wet AMD and dry AMD. It was known that development of wet AMD was followed by dry AMD. Dry AMD is referred to as the presence of macular degeneration due to pigmentary degeneration of retina and loss of retinal pigment epithelium (RPE). As the modified form of dry AMD, wet AMD shows conditions of subretinal neovascularization (subretinal scar), subretinal hemorrhage, detachment of RPE. In fact, subretinal neovascularization is meant to be a growing cicatricial tissue for a treatment of a space resulting from diseased RPE. Growth of neovascularization allows plasma and cellulose to be extruded therefrom, causing a small retinal detachment (Mousa S. A. et al., J Cell Biochem 74:135-43 (1999)). In addition, an injury caused by cicatrix of subretinal membrane may also result in weak eyesight.
Now, the method used to treat such ocular diseases includes laser treatment, laser photocoagulation, cryocoagulation and Visudyne (Edwin E. B. et al., Ophthalmology 88:101-107 (1981)). All of such treatments are carried out by surgery, but treatment by therapeutic agents still remains to be developed. Treatment by surgery has significant problems of incapable to be applied to all patients, and it also has disadvantages of having low healing possibilities and very expensive cost. Accordingly, most of patients, who may not receive a surgery, may come to blindness due to the lack of specific therapeutic agents. Also as human lives longer, these conditions continue to increase, but the therapeutic agents still remain to be developed. Thus, many studies and developments of angiogenesis inhibitors and therapeutic agents for treating the ocular diseases are still carried out. And examples of such agents include steroids, MMP inhibitor, antibodies against angiogenic growth factor and so on (Jeremy G. et al., Am J Pathology 160:1097-1103(2002)).